title: The role of phosphatidylinositol 3-kinase-δ in the immunomodulatory effects of lenalidomide in chronic lymphocytic leukemia.
abstract: In patients with chronic lymphocytic leukemia (CLL), lenalidomide can promote humoral immune responses but also induces a distinct disease-specific toxicity of tumor flare and cytokine release. These CLL-specific events result from increased expression of costimulatory molecules on B cells. Here we demonstrate that lenalidomide activation of CLL cells depends on the phosphatidylinositol 3-kinase p110δ (PI3K-δ) pathway. Inhibition of PI3K-δ signaling by the PI3K-δ-inhibiting drug, CAL-101, or by siRNA knockdown of p110δ, abrogates CLL cell activation, costimulatory molecule expression, and vascular endothelial growth factor and basic fibroblast growth factor gene expression that is induced by lenalidomide. In addition, CAL-101 attenuates lenalidomide-mediated increases in immunoglobulin M production by normal B cells. Collectively, these data demonstrate the importance of PI3K-δ signaling for lenalidomide immune modulation. These findings may guide development of strategies for the treatment of CLL that combine lenalidomide with CAL-101, with other inhibitors of the PI3K-δ pathway, or with other agents that target downstream kinases of this signaling pathway.
authors.affiliation: Integrated Biomedical Science Graduate Program, The Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Sarah E M
authors.initials: SE
authors.lastname: Herman
authors.forename: Rosa
authors.initials: R
authors.lastname: Lapalombella
authors.forename: Amber L
authors.initials: AL
authors.lastname: Gordon
authors.forename: Asha
authors.initials: A
authors.lastname: Ramanunni
authors.forename: Kristie A
authors.initials: KA
authors.lastname: Blum
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Jones
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lannutti
authors.forename: Kamal D
authors.initials: KD
authors.lastname: Puri
authors.forename: Natarajan
authors.initials: N
authors.lastname: Muthusamy
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
mesh_terms: D000970:Antineoplastic Agents / Q000276:immunology* / Q000494:pharmacology; D045744:Cell Line, Tumor; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology* / Q000494:pharmacology; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology* / Q000276:immunology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007155:Immunologic Factors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; D034741:RNA, Small Interfering; D013792:Thalidomide; D058543:Class Ia Phosphatidylinositol 3-Kinase; D000077269:Lenalidomide; C552946:idelalisib